. Mice with heritable hemolytic anemias, sph, ja, and nb, are models for human hereditary spherocytosis and elliptocytosis. Genetic mapping of the murine mutations shows tight linkage, if not identify, with structural genes essential for red blood cell integrity. The sph locus codes for alpha spectrin, ja for beta spectrin and nb for ankyrin. Further characterization of the mutations is dependent on acquisition of the complete and normal nucleotide coding sequence of the murine proteins. To this end, we have generated a reticulocyte library and are sequencing contiguous cDNA clones encoding each protein. This information will be used to identify sequence dissimilarities and to generate oligonucleotide primers for transcript amplification and peptide antibodies for protein dissection. Specific aims are (1) to isolate and sequence the entire cDNA of the normal erythrocyte proteins; (2) to identify the mutated nucleotides in nb/nb ankyrin; (3) to establish the relationship between normal ankyrin isoforms and the nb/nb thiol-protease sensitive 210 kD and the unique 150 kD reticulocyte ankyrins; (4) to determine the distribution of erythrocyte ankyrin in the brain and describe the neurological manifestations of its depletion in nb/nb mice; and (5) to characterize cytoskeletal changes accompanying normal nb/nb, ja/ja and sph/sph erythroid precursor ontogeny in utero.